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Semi‐Synthetic Mithramycin SA Derivatives with Improved AntiCancer Activity
Author(s) -
Scott Daniel,
Chen JhongMin,
Bae Younsoo,
Rohr Jürgen
Publication year - 2013
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12107
Subject(s) - chemistry , side chain , combinatorial chemistry , mutant , molecule , dna , small molecule , cancer cell , biochemistry , stereochemistry , cancer , gene , organic chemistry , biology , polymer , genetics
Mithramycin ( MTM ) is a potent anti‐cancer agent that has recently garnered renewed attention. This manuscript describes the design and development of mithramycin derivatives through a combinational approach of biosynthetic analogue generation followed by synthetic manipulation for further derivatization. Mithramycin SA is a previously discovered analogue produced by the M 7 W 1 mutant strain alongside the improved mithramycin analogues mithramycin SK and mithramycin SDK . Mithramycin SA shows decreased anti‐cancer activity compared to mithramycin and has a shorter, two carbon aglycon side chain that is terminated in a carboxylic acid. The aglycon side chain is responsible for an interaction with the DNA ‐phosphate backbone as mithramycin interacts with its target DNA . It was therefore decided to further functionalize this side chain through reactions with the terminal carboxylic acid in an effort to enhance the interaction with the DNA phosphate backbone and improve the anti‐cancer activity. This side chain was modified with a variety of molecules increasing the anti‐cancer activity to a comparable level to mithramycin SK . This work shows the ability to transform the previously useless mithramycin SA into a valuable molecule and opens the door to further functionalization and semi‐synthetic modification for the development of molecules with increased specificity and/or drug formulation.